FIRST NASAL VACCINE APPROVED FOR USE: On June 17, 2003, the Food and Drug Administration (FDA) approved the use of FluMist, an influenza vaccine that is the first nasally administered vaccine to be marketed in the United States. It is also the first live virus influenza vaccine approved in the U.S.

FluMist is approved to prevent influenza illness due to influenza A and B viruses in healthy children and adolescents, ages 5-17 years, and healthy adults, ages 18-49. In clinical trials, FluMist was evaluated in 20,228 individuals, including over 10,000 healthy children 5-17 years old. The efficacy of the vaccine in preventing influenza was approximately 87 percent among children included in the trial. In healthy adults ages 18-49 years, FluMist was effective in reducing severe illnesses with fever, and upper respiratory problems which may be caused by influenza infection.

As with any live virus vaccines, FluMist should not be given for any reason to people with immune suppression, including those with immune deficiency diseases, such as AIDS or cancer, and people who are being treated with drugs that cause immunosuppression. The safety of FluMist in people with asthma or other reactive airway diseases has not been established; FluMist should not be given to people with a history of these problems. In a large safety study, children under five years of age were found to have increased rate of asthma and wheezing within 42 days of vaccination compared to placebo recipients, and thus FluMist is not recommended for young children. For people age 50 years and over, the safe and effective use of FluMist has also not been established.

The vaccine should also not be administered to those with therapies including aspirin, a history of Guillain-Barre syndrome, chronic diseases, allergies to eggs or those who are pregnant. The most common adverse events associated with the vaccine were nasal congestion, runny nose, sore throat, and cough. FluMist is produced by MedImmune Vaccines and will be distributed by Wyeth. Both companies will market the product. For more information visit www.fda.gov or www.cdc.gov/nip

Tournier, BB, S Frelon, E Tourlonias, L Agez, O Delissen, I Dublineau, F Paquet, and F Petitot. 2009. Role of the olfactory receptor neurons in the direct transport of inhaled uranium to the rat brain.Toxicology Letters doi:10.1016/j.toxlet.2009.05.022. Synopsis by Paul Eubig, DVM Radioactive uranium that is inhaled by soldiers on the battlefield and by workers in factories may bypass the brain's protective barrier by following nerves from the nose directly to the brain. Nerves can act as a unique conduit, carrying inhaled uranium from the nose directly to the brain, finds a study with rats. Once in the brain, the uranium may affect task and decision-related types of thinking. This study provides yet another example of how some substances can use the olfactory system – bypassing the brain's protective blood barrier – to go directly to the brain. Titanium nanoparticles and the metals manganese, nickel, and thallium have been shown to reach the brian using the same route. Military personnel and people who work in uranium processing plants are exposed to the weak radioactive element via wounds or by breathing. Exposure may affect brain function; cognitive skills are lowered in soldiers who carry uranium-laced shrapnel. Uranium has various industrial and military uses. A form of uranium called depleted uranium is very dense and is used in armor-piercing ammunition and military vehicle armor. Battlefield exposure can occur through wounds – such as with some US military personnel who were injured during the Gulf War. These exposures can be higher than with civilians who work with the element. A study of Gulf War veterans who have uranium shrapnel in their bodies showed that they perform more poorly on general brain cognitive tests of performance efficiency and accuracy. Uranium can also be inhaled. Soldiers in vehicles hit by uranium rounds and workers in uranium-processing facilities can breathe it in. The researchers – taking advantage of the fact that uranium can exist in different forms, or isotopes – used rats to compare how the element travels through the body if it is inhaled or injected into the blood. The animals breathed in one isotope at levels similar to those encountered on a battlefield where depleted uranium weapons are used. They were also injected with a different isotope. Researchers compared the levels of the two isotopes in different regions of the brain. The inhaled isotope accumulated at 2 to 3 times higher levels than the injected isotope in the olfactory (smell) paths from the nose to the brain and in the frontal cortex and hypothalamus of the brain. This is concerning because the front part of the brain controls executive function, which is the broad ability to gather information, make decisions and initiate action. The scientists then chemically damaged the olfactory nerves in the nose. The rats with the damaged nerves had three times less uranium in the olfactory system than the rats with intact olfactory nerves. These finding suggests that inhaled uranium can travel directly from the nose along the olfactory nerves to the front of the brain. The olfactory pathway, then, plays an important role in inhaled uranium reaching the brain. It is not known from this study if soldiers and civilian workers that breathe uranium could be at an even higher risk for cognitive effects or if inhaled uranium may affect brain function in similar ways as when it is carried through the blood. It is also unclear if these findings would hold true for the human brain since the rat brain is much more developed for smelling than the human brain. Assessing these possible risks and determining if people's relatively underdeveloped sense of smell could protect the brain would require further studies of people exposed to uranium through inhalation A study with rats suggests that radioactive uranium inhaled by soldiers on the battlefield and by workers in factories may bypass the brain's protective barrier by following nerves from the nose directly to the brain. This study provides yet another example of how some substances can use the olfactory system to bypass the brain's protective blood barrier and go directly to the brain. Titanium nanoparticles and the metals manganese, nickel, and thallium use the same route. more…

FluMist is approved to prevent influenza illness due to influenza A and B viruses in healthy children and adolescents, ages 5-17 years, and healthy adults, ages 18-49 years.

What is the difference between live attenuated influenza virus (LAIV) and the flu shot that is made from inactivated viruses?

LAIV and inactivated influenza vaccine contain strains of influenza viruses that are matched to protect against influenza strains that are likely to circulate each year. Viruses for both vaccines are grown in eggs. Both vaccines are administered annually to provide optimal protection against influenza infection. Inactivated vaccines are produced by killing the flu viruses. The killed viruses cannot cause influenza.

LAIV contains attenuated (or weakened) viruses. These weakened strains usually do not cause illness because they have lost virulence (disease-causing properties). There is, however, a possibility that they can still reproduce and cause disease, especially in persons with weakened immune systems.

FluMist (LAIV) is administered intranasally by sprayer, whereas inactivated influenza vaccine is administered intramuscularly by injection. FluMist (LAIV) is approved for use only among healthy persons aged 5-49 years; inactivated influenza vaccine is approved for use among persons aged >6 months, including those who are healthy and those with medical conditions.

Since the flu shot is recommended for many people over the age of 49, why isn’t FluMist recommended for individuals 50 years of age and older?

Studies with FluMist did not include enough patients over the age of 49 to determine if they respond differently than younger individuals. Therefore, the safe and effective use of FluMist in persons 50 years and older has not been established.

How many doses are recommended per season?

Children 5-8 years old need two doses at least 6 weeks apart in their first year of vaccination with FluMist.

Individuals 9-49 years old need only one dose.

How well does this vaccine work?

The vaccine prevented influenza associated illness in approximately 87% of the children included in the trial.

Adults (ages 18-49 years) who received FluMist experienced significantly fewer episodes of severe febrile illness (SFI) when compared to those who received placebo. Severe febrile illness was defined as having at least three days of symptoms (runny nose, sore throat, cough, muscle aches, tiredness/weakness) and one day of fever.

Adults who received FluMist did not experience a significant reduction in any febrile illness (AFI). Adults were characterized as having AFI if they had symptoms for at least two consecutive days, with fever on at least one day.

As with any vaccine, FluMist may not protect 100% of individuals receiving the vaccine.

However, a vaccine, like any medicine, is capable of causing serious problems, such as severe allergic reactions. The risk of a vaccine causing serious harm, or death, is extremely small, and serious problems from flu vaccine are rare.

Are there certain people who should not receive FluMist?

As with any medication, individuals should check with their health care provider before receiving any flu vaccines. According to the approved package insert, the following people should not get the intranasal influenza vaccine:

Adults 50 years of age or older, or children younger than 5 should not receive FluMist.

FluMist should not be given for any reason to people with immune suppression, including those with immune deficiency diseases, such as AIDS or cancer, and people who are being treated with drugs that cause immunosuppression.

The safety of FluMist in people with asthma or other reactive airway diseases has not been established, and therefore, is not recommended for use in patients with a history of reactive airway problems.

Additionally, FluMist should not be given to people with chronic underlying medical conditions that may predispose them to severe flu infections. For these people, the injected vaccine is indicated.

Individuals with egg allergies should not receive this or any other flu vaccine.

People who have health problems associated with heart disease, kidney disease, lung disease, or metabolic diseases such as diabetes, anemia and other blood disorders should not receive FluMist.

Because Reye syndrome in children has been associated with administration of aspirin during influenza virus infections, FluMist is not recommended in children and adolescents 5-17 years of age if they are receiving aspirin or aspirin-containing therapy.

Pregnant women (in their second or third trimesters during influenza season) should not receive FluMist.

Anyone with a history of Guillain-Barré Syndrome (GBS) should not receive FluMist.

Physicians, nurses, family members, or anyone else coming in close contact with anyone with a weakened immune system should not receive FluMist. If I receive FluMist, is it possible that I will get the flu from the vaccine?

Yes, although strains of attenuated vaccines are weakened, there is a possibility that they can still reproduce and cause disease, particularly in people with weakened or compromised immune systems.

Can I get the flu from the inactivated vaccine?

No. Components in the inactivated influenza vaccine are made from killed influenza viruses, and they cannot cause influenza infection.

What is the best time of year to receive the flu vaccine?

Flu vaccines should be administered prior to exposure to influenza. The peak of influenza activity varies from year to year, but generally occurs in the U.S. between late December and early March. Influenza vaccines usually become available in early October, but contact your healthcare provider for additional information.

Will I need to receive a vaccine every year?

Because yearly variation in the influenza strains is possible, annual revaccination with FluMist, as well as with the inactivated vaccine, is recommended.

If I would like to obtain additional information where can I find it?

We recommend that that you talk to your health care provider when you have any questions related to the medication(s) you receive. He or she can also suggest other sources of information.

Package Insert (Circular) 16 June 2003 Page 1 of 19 Influenza Virus Vaccine Live, Intranasal FluMistTM 2003-2004 Formula FOR NASAL ADMINISTRATION ONLY Rx only DESCRIPTION Influenza Virus Vaccine Live, Intranasal (FluMist™) is a live trivalent nasally administered vaccine intended for active immunization for the prevention of influenza. Each 0.5 mL dose is formulated to contain 106.5-7.5 TCID50 (median tissue culture infectious dose) of live attenuated influenza virus reassortants of the strains recommended by the U.S. Public Health Service (USPHS) for the 2003-2004 season: A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2) (A/Moscow/10/99-like), and B/Hong Kong/330/2001 [1]. These strains are (a) antigenically representative of influenza viruses that may circulate in humans during the 2003-2004 influenza season; (b) cold-adapted (ca) (i.e., they replicate efficiently at 25oC, a temperature that is restrictive for replication of many wild-type viruses); (c) temperaturesensitive (ts) (i.e., they are restricted in replication at 37oC (Type B strains) or 39oC (Type A strains), temperatures at which many wild-type influenza viruses grow efficiently); and (d) attenuated (att) so as not to produce classic influenza-like illness in the ferret model of human influenza infection. The cumulative effect of the antigenic properties and the ca, ts, and att phenotype is that the vaccine viruses replicate in the nasopharynx to produce protective immunity.

Each of the three influenza virus strains contained in FluMist is a genetic reassortant of a Master Donor Virus (MDV) and a wild-type influenza virus. The MDVs (A/Ann Arbor/6/60 and B/Ann Arbor/1/66) were developed by serial passage at sequentially lower temperatures in specific pathogen-free (SPF) primary chick kidney cells [2]. During this process, the MDVs acquired the ca, ts and att phenotype and multiple mutations in the gene segments that encode viral proteins other than the surface glycoproteins. The individual contribution of the genetic sequences of the six non-glycoprotein MDV genes (“internal gene segments”) to the ca, ts, and att phenotype is not completely understood. However, at least five genetic loci in three different internal gene segments of the Type A MDV and at least three genetic loci in two different internal gene segments of the Type B MDV contribute to the ts property [3, 4]. For each of the three strains in FluMist, the six internal gene segments responsible for ca, ts, and att phenotypes are derived from the MDV, and the two segments that encode the two surface glycoproteins, hemagglutinin Package Insert (Circular) 16 June 2003 Page 2 of 19 (HA) and neuraminidase (NA), are derived from the corresponding antigenically relevant wild-type influenza viruses that have been recommended by the USPHS for inclusion in the annual vaccine formulation. Thus, the three viruses contained in FluMist maintain the replication characteristics and phenotypic properties of the MDV and express the HA and NA of wild-type viruses that are related to strains expected to circulate during the 2003-2004 influenza season.

Viral harvests used in the production of FluMist are produced by inoculating each of the three reassortant viruses into specific pathogen-free (SPF) eggs that are incubated to allow for vaccine virus replication. The allantoic fluid of these eggs is harvested, clarified by centrifugation, and stabilized with buffer containing sucrose, potassium phosphate, and monosodium glutamate (0.47 mg/dose). Viral harvests from the three strains (H1N1, H3N2, and B) are subsequently blended and diluted to desired potency with allantoic fluid derived from uninfected SPF eggs to produce trivalent bulk vaccine. Each lot of viral harvest is tested for ca, ts, and att and is also tested extensively by in vitro and in vivo methods to detect adventitious agents. The bulk vaccine is then filled directly into individual sprayers for nasal administration. These sprayers are labeled and stored at ≤-15oC.

Gentamicin sulfate is added early in the manufacturing process during preparation of reassortant viruses at a calculated concentration of approximately 1 µg/mL. Later steps of the manufacturing process do not use gentamicin, resulting in a diluted residual concentration in the final product of <0.015 µg/mL (limit of detection of the assay). FluMist does not contain any preservatives. Each pre-filled FluMist sprayer contains a single 0.5 mL dose. The teflon tip attached to the sprayer is equipped with a one-way valve that produces a fine mist that is primarily deposited in the nose and nasopharynx. When thawed for administration, FluMist is a colorless to pale yellow liquid and is clear to slightly cloudy (see DOSAGE AND ADMINISTRATION).

CLINICAL PHARMACOLOGY Influenza is a highly infectious respiratory viral infection that causes recurrent winter epidemics of acute disease in persons of all ages. Highest rates of illness are generally reported among 5-14 year-olds [5, 6]. Among healthy individuals 15-44 years of age, the average rate of excess hospitalizations attributable to influenza is 20-25 per 100,000 per year [7], with an annual influenza-associated mortality rate of 0.2-1.5 per 100,000 person-years [8]. Types A and B influenza viruses are the principal causes of influenza in humans. Type A influenza viruses are divided into subtypes on the basis of the two surface antigens, hemagglutinin (HA) and neuraminidase (NA), while influenza virus B is classified as a single subtype. Continuous mutation of the influenza virus genome leads to an accumulation of genetic and accompanying antigenic changes that result in the evolution of viruses into recognizable antigenic lineages or strains within a subtype. Protective immune responses following natural Package Insert (Circular) 16 June 2003 Page 3 of 19 infection result in population-based immunity to circulating strains. However, this immune barrier eventually results in the emergence of strains that have undergone antigenic change, or “drift.” Because these “drifted” strains can escape immunity to HA and NA antigens of previously circulating strains, experience with inactivated influenza vaccines suggests that vaccines may require annual updating to match the contemporary strains. Vaccination is the principal means of prevention of influenza and influenza-associated complications [1].

Mechanism of Action Immune mechanisms conferring protection against influenza following receipt of FluMist vaccine are not fully understood. Likewise, naturally acquired immunity to wild-type influenza has not been completely elucidated. Serum antibodies, mucosal antibodies and influenza-specific T cells may play a role in prevention and recovery from infection [9, 10]. Vaccination with FluMist has been demonstrated to induce influenza strain-specific serum antibodies [11, 12].Clinical Studies FluMist was administered to 20,228 subjects in clinical studies. The population evaluated included 10,297 healthy children 5-17 years of age (14,058 doses of FluMist received) and 3297 healthy adults 18-49 years of age (3335 doses of FluMist received) who received at least one dose of vaccine. Second and third annual doses have been given to 1766 and 128 children 5-17 years of age, respectively. In randomized, placebo-controlled trials, 4719 healthy children 5-17 years of age and 2864 healthy adults 18-49 years of age received FluMist.

The efficacy of FluMist against culture-confirmed influenza disease for Types A/H3N2 and B was assessed in a field trial in children. The effectiveness of FluMist against Types A/H3N2 and B, defined as a reduction in influenza-like illness and illness-associated health care utilization, was assessed in a field trial in adults. Type A/H1N1 did not circulate during either trial, and no field efficacy data against this strain are available.Pediatric Study The Pediatric Efficacy Study was a multi-center, randomized, double-blind, placebo-controlled trial performed in healthy U.S. children to evaluate the efficacy of FluMist against cultureconfirmed influenza over two successive seasons [13, 14]. The primary endpoint for the first year of the trial was the prevention of culture-confirmed influenza illness due to antigenically matched wild-type influenza in healthy children who received two doses of vaccine. During the first year of the study a subset of 312 children 60-71 months of age were randomized 2:1 (vaccine:placebo). All children with culture-confirmed influenza experienced respiratory symptoms (cough, runny Package Insert (Circular) 16 June 2003 Page 4 of 19 nose, or sore throat) and most experienced fever (68%), health care provider visits (68%), and missed school days (74%). As shown in Table 1, when compared with placebo recipients, FluMist recipients 60-71 months of age who received two doses of vaccine (n=238) experienced a significant reduction in the incidence of culture-confirmed influenza (efficacy 87.4%, 95% CI: 59.4, 97.9). In the 60-71 month old age group, children who received one dose of FluMist when compared to one dose of placebo experienced a significant reduction in the incidence of culture-confirmed influenza (0 of 54 FluMist recipients vs 3 of 20 placebo recipients; efficacy 100%, 95% CI: 47.0, 100). Approximately 85% of the participants in the first year returned for the second year of the Pediatric Efficacy Study, including a subset of 544 children 60-84 months of age [4]. During the second year of the trial, the H3N2 strain included in the vaccine was A/Wuhan/359/95. However, the H3N2 strain that primarily circulated was A/Sydney/05/97, which differed antigenically from A/Wuhan/359/95. Type A/Wuhan/359/95 (H3N2) also circulated as did Type B strains. Children remained in the same treatment group as in year one and received a single dose of FluMist or placebo. The primary endpoint of the trial was the prevention of culture-confirmed influenza illness due to antigenically matched wild-type influenza after a single annual revaccination dose of FluMist. In the subset of 544 children 60-84 months of age, illness associated with culture-confirmed illness in the second year was similar in scope and severity to that in the first year. The overall efficacy of FluMist against culture-confirmed wild-type influenza, regardless of antigenic match, was 86.9% (95% CI: 70.8, 94.1). Table 1 Efficacy of FluMist Against Culture-Confirmed Influenza in Children ≥ 60 Months of Age Endpoint Cases Efficacy (%) (95% CI) FluMist Placebo Year One (60 – 71 mo of age) N=163 n (%) N= 75 n (%) Culture-confirmed influenzaa 3 (1.8) 11 (14.7) 87.4 (59.4, 97.9)* Year Two (60 – 84 mo of age) N=375 n (%) N=169 n (%) Culture-confirmed influenzaa,b 7 (1.9) 24 (14.2) 86.9 (70.8, 94.1)* * Denotes statistically significant, p≤0.05. a Overall efficacy against Type A (H3N2) and Type B wild-type viruses. Field efficacy against wild Type A (H1N1) viruses could not be determined because those strains did not circulate during the study period. b Includes illness caused by A/Sydney/05/97 (H3N2), an antigenic variant not included in the vaccine.

Package Insert (Circular) 16 June 2003 Page 5 of 19 Studies in Adults The Adult Effectiveness Study was a multi-center, randomized, double-blind, placebo-controlled trial in which healthy adults were enrolled, including 3920 adults 18-49 years of age (2150 women and 1770 men). Participants were randomized 2:1, vaccine:placebo. The trial was designed to evaluate the effectiveness of FluMist in the reduction of influenza-like illness during the peak influenza outbreak period at each site, based on community surveillance [15]. Cultures for influenza virus were not obtained from subjects in the trial, so that the efficacy against cultureconfirmed influenza was not assessed. The predominant circulating strain of influenza virus during the trial period was A/Sydney/05/97 (H3N2), a strain that differed antigenically from the A/Wuhan/359/95 (H3N2) strain contained in FluMist. Type A/Wuhan (H3N2) and Type B strains also circulated in the U.S. during the study period. The primary endpoint of the trial was the reduction in the proportion of participants with one or more episodes of any febrile illness (AFI). Two other, more specific febrile influenza-like illness definitions were also prospectively assessed: severe febrile illness (SFI), and febrile upper respiratory illness (FURI). Adults were characterized as having AFI if they had symptoms for at least two consecutive days with fever on at least one day and if they had two or more symptoms (fever, chills, headache, runny nose, sore throat, cough, muscle aches, tiredness/weakness) on at least one day. SFI was defined as having at least three consecutive days of symptoms, at least one day of fever, and two or more symptoms on at least three days. FURI was defined as at least two consecutive days of upper respiratory infection (URI) symptoms (runny nose, sore throat, or cough), fever on at least one day, and at least two URI symptoms on at least one day. Adults meeting the three illness definitions often had associated health care provider visits (25-31%), used antibiotics (28-32%), and missed at least one day of work (51-58%).

During the seven-week site-specific outbreak period, in the subset of subjects age 18-49 years, FluMist recipients did not experience a significant reduction in AFI; significant reductions were observed for SFI and FURI (Table 2). An additional measure of the severity of disease was illness associated days of health care provider visits; FluMist recipients experienced significant reductions in days of health care provider visits associated with SFI (17.8%, 95% CI: 2.0, 31.0), and FURI (36.9%, 95% CI: 24.4, 47.3) when compared to placebo recipients. However, no significant reduction in days of health care provider visits associated with AFI was observed among FluMist recipients when compared to placebo recipients. Package Insert (Circular) 16 June 2003 Page 6 of 19 Table 2 Effectiveness of FluMist in Adults 18–49 Years of Age During the 7-week Site-Specific Outbreak Period Endpoint FluMist N=2411a n (%) Placebo N=1226a n (%) Percent Reduction (95% CI) Participants with one or more events of:b Any febrile illness 331 (13.73) 189 (15.42) 10.9 (-5.1, 24.4) Severe febrile illness 250 (10.37) 158 (12.89) 19.5 (3.0, 33.2)* Febrile upper respiratory illness 213 ( 8.83) 142 (11.58) 23.7 (6.7, 37.5)* * Denotes p-value ≤0.05. Note: The proportion of participants with any febrile illness (AFI) was the primary study endpoint; effectiveness was not demonstrated for this endpoint (p-value >0.05). a Number of evaluable subjects (92.7% and 93.0% of FluMist and placebo recipients, respectively). b The predominantly circulating virus during the trial period was A/Syndey/05/97 (H3N2), an antigenic variant not included in the vaccine. Challenge Study The ability of FluMist to protect adults from influenza illness after challenge with wild-type influenza was assessed in a multi-center, randomized, double-blind, placebo-controlled trial in healthy adults 18-41 years of age who were serosusceptible to at least one strain included in the vaccine [12]. Adults were randomized to receive FluMist (n=29) or placebo (n=31). Each subject was challenged intranasally with only a single strain of wild-type virus (Type A/H3N2, Type A/H1N1 or Type B) to which he/she was serosusceptible, and the results were pooled for all three strains combined within each treatment group. Laboratory-documented influenza illness due to all three strains combined was reduced compared to placebo by 85% (95% CI: 28, 100) in FluMist recipients. Transmission FluMist contains live attenuated influenza viruses that replicate in the nasopharynx of the recipient and are shed in respiratory secretions. Assessing the probability that these shed vaccine viruses will be transmitted from a vaccinated individual to a non-vaccinated individual was the primary objective of a prospective, randomized, double-blind, placebo-controlled trial in a daycare setting in Finland [16]. Children enrolled in the study attended daycare at least three days per week for four hours per day, and were in a playroom with at least four children, at least one of whom was vaccinated with FluMist. A total of 197 children 8-36 months of age were randomized to receive one dose of FluMist (n=98) or placebo (n=99). Virus shedding was evaluated for 21 days by culture of nasal swabs obtained from each subject approximately three times per week. Wild-type A (H3N2) influenza virus was documented to have circulated in the Package Insert (Circular) Now, having read this sheds for 21 days, read this article and find out how to cause a pandemic. 16 June 2003 Page 7 of 19 community and in the study population during the trial, whereas Type A (H1N1) and Type B strains did not. Eighty percent of FluMist recipients shed at least one vaccine strain, with a mean duration of shedding of 7.6 days (range 1-21 days). The cold-adapted (ca) and temperature-sensitive (ts) phenotypes were preserved in all shed viruses tested (n=135 tested of 250 strains isolated at the local laboratory). A total of seven placebo subjects shed 10 influenza isolates. One placebo subject shed a Type B virus confirmed to be a vaccine strain. This Type B isolate retained the ca, ts, and att phenotypes of the vaccine strain, and had the same genetic sequence when compared to a Type B virus shed by a vaccine recipient within the same playgroup. Six placebo subjects shed nine isolates identified as Type A, two of these subjects had two cultures that grew Type A strains (four isolates) confirmed as wild-type A/Panama (H3N2). The remaining four placebo subjects shed Type A isolates that could not be further characterized, and thus vaccine strains could not be excluded.

Assuming that a single transmission event occurred (isolation of the Type B vaccine strain), the probability of a young child acquiring vaccine virus following close contact with a single FluMist vaccinee in this daycare setting was 0.58% (95% CI: 0, 1.7) based on the Reed Frost model [17]. With documented transmission of one Type B in one placebo subject and possible transmission of Type A viruses in four placebo subjects, the probability of acquiring a transmitted vaccine virus was estimated to be 2.4% (95% CI: 0.13, 4.6), using the Reed Frost model. The frequency and duration of shedding FluMist viral strains by individuals 5-49 years of age has not been established. INDICATIONS AND USAGE FOR NASAL ADMINISTRATION ONLY FluMist is indicated for active immunization for the prevention of disease caused by influenza A and B viruses in healthy children and adolescents, 5-17 years of age, and healthy adults, 18-49 years of age. FluMist is not indicated for immunization of individuals less than 5 years of age, or 50 years of age and older, or for therapy of influenza, nor will it protect against infections and illness caused by infectious agents other than influenza A or B viruses. CONTRAINDICATIONS Under no circumstances should FluMist be administered parenterally. Individuals with a history of hypersensitivity, especially anaphylactic reactions, to any component of FluMist, including eggs or egg products, should not receive FluMist (see DESCRIPTION). Package Insert (Circular) 16 June 2003 Page 8 of 19 FluMist is contraindicated in children and adolescents (5-17 years of age) receiving aspirin therapy or aspirin-containing therapy, because of the association of Reye syndrome with aspirin and wild-type influenza infection. FluMist should not be administered to individuals who have a history of Guillain-Barré syndrome. As with other live virus vaccines, FluMist should not be administered to individuals with known or suspected immune deficiency diseases such as combined immunodeficiency, agammaglobulinemia, and thymic abnormalities and conditions such as human immunodeficiency virus infection, malignancy, leukemia, or lymphoma. FluMist is also contraindicated in patients who may be immunosuppressed or have altered or compromised immune status as a consequence of treatment with systemic corticosteroids, alkylating drugs, antimetabolites, radiation, or other immunosuppressive therapies. WARNINGS The safety of FluMist in individuals with asthma or reactive airways disease has not been established. In a large safety study in children 1-17 years of age, children <5 years of age who received FluMist were found to have an increased rate of asthma within 42 days of vaccination when compared to placebo recipients (see ADVERSE REACTIONS). FluMist should not be administered to individuals with a history of asthma or reactive airways disease. The safety of FluMist in individuals with underlying medical conditions that may predispose them to severe disease following wild-type influenza infection has not been established. FluMist is not indicated for these individuals. According to the Advisory Committee on Immunization Practices (ACIP), such individuals include, but are not limited to, adults and children with chronic disorders of the cardiovascular and pulmonary systems, including asthma; pregnant women who will be in their second or third trimesters during influenza season; adults and children who required regular medical follow-up or hospitalization during the preceding year because of chronic metabolic diseases (including diabetes), renal dysfunction, or hemoglobinopathies; and adults and children with congenital or acquired immunosuppression caused by underlying disease or immunosuppressive therapy (see CONTRAINDICATIONS). Intramuscularly administered inactivated influenza vaccines are available to immunize high-risk individuals [1]. As with any vaccine, FluMist may not protect 100% of individuals receiving the vaccine. PRECAUTIONS General CARE IS TO BE TAKEN BY THE HEALTH CARE PROVIDER FOR THE SAFE AND EFFECTIVE USE OF THIS PRODUCT. Package Insert (Circular) 16 June 2003 Page 9 of 19 Prior to administration of FluMist, individuals or their parent/guardian should be asked about their current health status, their personal medical history and the medical history of household and close contacts, including immune status, to determine the existence of any contraindications (see CONTRAINDICATIONS and WARNINGS) to immunization with FluMist. FluMist recipients should avoid close contact (e.g., within the same household) with immunocompromised individuals for at least 21 days. EPINEPHRINE INJECTION (1:1000) OR COMPARABLE TREATMENT MUST BE READILY AVAILABLE IN THE EVENT OF AN ACUTE ANAPHYLACTIC REACTION FOLLOWING VACCINATION. The health care provider should ensure prevention of any allergic or other adverse reactions by reviewing the individual's history for possible sensitivity to influenza vaccine components, including eggs and egg products. Administration of FluMist should be postponed until after the acute phase (at least 72 hours) of febrile and/or respiratory illnesses. Information for Vaccine Recipients or Parents/Guardians Vaccine recipients or their parents/guardians should be informed by the health care provider of the potential benefits and risks of FluMist, and the need for two doses for the first use of FluMist in 5-8 year olds. Due to the possible transmission of vaccine virus, vaccine recipients or their parents/guardians should be advised to avoid close contact (e.g., within the same household) with immunocompromised individuals for at least 21 days. The vaccine recipient or the parent/guardian accompanying the vaccine recipient should be told to report any suspected adverse events to the physician or clinic where the vaccine was administered (see ADVERSE EVENT REPORTING). Drug Interactions Children or adolescents who are receiving aspirin therapy or aspirin-containing therapy should not receive FluMist (see CONTRAINDICATIONS). FluMist should not be administered to persons on immunosuppressive therapy. The concurrent use of FluMist with antiviral compounds that are active against influenza A and/or B viruses has not been evaluated. However, based upon the potential for interference between such compounds and FluMist, it is advisable not to administer FluMist until 48 hours after the cessation of antiviral therapy and that antiviral agents not be administered until two weeks after administration of FluMist unless medically indicated.

There are no data regarding co-administration of FluMist with other intranasal preparations, including steroids. Package Insert (Circular) 16 June 2003 Page 10 of 19 Concurrent Administration with Other Vaccines The safety and immunogenicity of FluMist when administered concurrently with other vaccines have not been determined. Therefore, FluMist should not be administered concurrently with other vaccines. Studies of FluMist in healthy individuals excluded subjects who received any live virus vaccine within one month of enrollment and any inactivated or subunit vaccine within two weeks of enrollment; therefore, health care providers should adhere to these intervals when administering FluMist. Laboratory Interactions Data related to shedding of FluMist in children and adults are limited. Nasopharyngeal secretions or swabs collected from vaccinees may test positive for influenza virus for up to three weeks. Carcinogenesis, Mutagenesis, Impairment of Fertility FluMist has not been evaluated for its carcinogenic or mutagenic potential or its potential to impair fertility. Pregnancy (Category C) Animal reproduction studies have not been conducted with FluMist. It is also not known whether FluMist can cause fetal harm when administered to a pregnant woman or affect reproduction capacity. Therefore, FluMist should not be administered to pregnant women. Nursing Mothers It is not known whether FluMist is excreted in human milk. Therefore, as some viruses are excreted in human milk and additionally, because of the possibility of shedding of vaccine virus and the close proximity of a nursing infant and mother, caution should be exercised if FluMist is administered to nursing mothers. Pediatric Use The safety of FluMist in infants and children <60 months of age has not been established (see CLINICAL STUDIES, INDICATIONS AND USAGE, and ADVERSE REACTIONS). Geriatric Use Clinical studies with FluMist did not include sufficient numbers of adults age 65 years and older to determine if they respond differently from younger individuals. The safe use of FluMist in persons 65 years and older has not been established (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Package Insert (Circular) 16 June 2003 Page 11 of 19 ADVERSE REACTIONS See CLINICAL STUDIES for a description of the number of participants in clinical trials. Serious Adverse Events Across all clinical trials, serious adverse events (SAEs) were monitored after vaccination for 42 days in children and for 28 days in adults. SAEs occurred at a similar rate (<1%) in FluMist and placebo recipients for both healthy children and healthy adults. Overall, across the placebo-controlled trials in adults and children, the incidence of selected adverse reactions that may be complications of influenza (such as pneumonia, bronchitis, bronchiolitis, or central nervous system events) was similar in FluMist and placebo groups. Adverse Events in Placebo-Controlled Trials In all placebo-controlled studies, allantoic fluid from uninfected eggs was used as the placebo. In randomized, placebo-controlled trials, 4719 healthy children 5-17 years of age and 2864 healthy adults 18-49 years of age received FluMist and 2327 healthy children and 1454 healthy adults received the placebo. In placebo-controlled clinical trials conducted in healthy populations, solicited adverse events and daily temperatures were collected on diary cards. These solicited events included runny nose/nasal congestion, sore throat, cough, irritability, headache, chills, vomiting, muscle aches, and decreased activity and a feeling of tiredness/weakness. Solicited Adverse Events in Children Table 3 shows an analysis of solicited events for the Pediatric Efficacy Study in the subset of healthy children 60-71 months of age. The largest absolute differences between FluMist and placebo after Dose One were observed in the incidences of headache and runny nose/nasal congestion. No differences were observed for fever (>100°F oral). Following Dose Two, the largest absolute differences between FluMist and placebo were runny nose/nasal congestion and cough. Package Insert (Circular) 16 June 2003 Page 12 of 19 Table 3 Summary of Solicited Events Observed within 10 Days after Each Dose for Vaccine and Placebo Recipients; Healthy Children 60–71 Months of Age Post-Dose One Post-Dose Two FluMist Placebo FluMist Placebo 214a 95a 161a 75a Event % % % % Any event 65.4 61.4 66.5 53.3 Cough 26.8 32.7 38.5 30.7 Runny Nose/ Nasal Congestion 48.1 44.2 46.0 32.0 Sore Throat 12.6 19.8 9.3 16.0 Irritability 19.5 16.8 9.9 9.3 Headache 17.8 11.6 6.8 16.0 Chills 6.1 5.3 2.5 4.0 Vomiting 4.7 3.2 5.6 12.0 Muscle Aches 6.1 4.2 5.0 4.0 Decreased Activity 14.0 12.6 10.6 13.3 Feverb Temp 1 9.5 9.9 4.3 4.0 Temp 2 2.2 2.0 0.6 1.3 Temp 3 0.0 0.0 0.0 0.0 Note: There were no statistically significant differences in any of these events (p-value >0.05); Fisher’s Exact method. a Number of evaluable subjects (those who returned diary cards) for each event. b Fever Temp 1: Oral >100°F, rectal or aural >100.6°F, or axillary >99.6°F. Temp 2: Oral >102°F, rectal or aural >102.6°F, or axillary >101.6°F. Temp 3: Oral >104°F, rectal or aural >104.6°F, or axillary >103.6°F. For the cohort of 128 children who received FluMist across three consecutive years, rates of solicited adverse events were not significantly increased when compared to placebo recipients [4]. Other Adverse Events in Children In addition to the solicited events, parents also reported other adverse events that occurred during the course of the clinical trials. Among healthy children age 60-71 months in the Pediatric Efficacy Study, the events that occurred in at least 1% of FluMist recipients and at a higher rate compared to placebo were: abdominal pain (3.7% FluMist vs 0% placebo), otitis media (1.4% FluMist vs 0% placebo), Package Insert (Circular) 16 June 2003 Page 13 of 19 accidental injury (2.3% FluMist vs 2.1% placebo), diarrhea (3.7% FluMist vs 1.1% placebo),following Dose One and otitis media (3.1% FluMist vs 1.3% placebo) following Dose Two. None of these differences were statistically significant. Medically Attended Events in Children and Adolescents A large randomized, double-blind, placebo-controlled trial in healthy children 1 through 17 years of age was conducted at 31 clinics in the Northern California Kaiser-Permanente Health Maintenance Organization (HMO) to assess the rate of medically attended events (MAEs) within 42 days of vaccination. Participants were randomized 2:1 (vaccine:placebo). A total of 6657 evaluable children 5-17 years of age were enrolled, including 3244 boys and 3413 girls. Of these 6657 children, 2606 were 5-8 years of age and 4051 were 9-17 years of age. Dose Two for children less than nine years of age was to be administered 28 to 42 days after Dose One. Data regarding MAEs were obtained from the Kaiser-Permanente computerized health care utilization databases for hospitalizations, emergency department visits and clinical visits. MAEs were analyzed individually and within four pre-specified grouped diagnoses: acute respiratory tract events, systemic bacterial infections, acute gastrointestinal tract events, and rare events potentially related to influenza. For these four pre-specified grouped diagnoses, no significant increase in risk for FluMist recipients was seen in the combined analyses across all utilization settings, doses, and age groups. Selected respiratory tract illnesses of special interest (pneumonia, bronchitis, bronchiolitis, and croup) were included in acute respiratory tract events and were not associated with increased risk for FluMist recipients in any protocol-specified analysis. No systemic bacterial infection occurred. In FluMist recipients, an increased risk was not observed for rare events that have been reported with naturally occurring influenza virus infection, including seizures(s), febrile seizures, and epilepsy. No cases of encephalitis, acute idiopathic polyneuritis (Guillain-Barré syndrome), Reye syndrome, or myocarditis (influenzaassociated rare disorders) were reported in this study. In this study, in individuals 5-17 years of age, four individual MAEs were significantly increased and 11 were significantly decreased. Of the four individual MAEs associated with increased risk, a biological association with FluMist is plausible for one: abdominal pain. Of the 11 individual MAEs associated with decreased risk, a biologically plausible association with FluMist exists for seven: asthma, bronchitis, conjunctivitis, cough, viral syndrome, otitis media, and wheezing/shortness of breath. However, in the same study, a statistically significant increase in asthma or reactive airways disease was observed for children 12-59 months of age following Dose One (Relative Risk 3.53, 90% CI: 1.1,15.7). As a result of this finding, FluMist is not indicated for children <60 months of age. Package Insert (Circular) 16 June 2003 Page 14 of 19 Solicited Adverse Events in Adults In the placebo-controlled Adult Effectiveness Study, the rate of solicited adverse events in the subset of healthy adults 18-49 years of age are shown in Table 4. Statistically significant differences were observed for any event, cough, runny nose, sore throat, chills, and tiredness/weakness. Fever >100° F was similar in FluMist and placebo recipients after a single dose. Table 4 Summary of Solicited Events Observed within 7 Days after Each Dose for Vaccine and Placebo Recipients; Healthy Adults 18–49 Years of Age FluMist Placebo N=2548a N=1290a Event (%) (%) Any event 71.9* 62.6 Cough 13.9* 10.8 Runny Nose 44.5* 27.1 Sore Throat 27.8* 17.1 Headache 40.4 38.4 Chills 8.6* 6.0 Muscle Aches 16.7 14.6 Tiredness/Weakness 25.7* 21.6 Fever Oral Temp >100°F 1.5 1.3 Oral Temp >101°F 0.5 0.7 Oral Temp >102°F 0.1 0.2 Oral Temp >103°F 0.0 0.0 * Denotes statistically significant p-value ≤0.05; no adjustments for multiple comparisons; Fisher’s Exact Method. a Number of evaluable subjects (those who returned diary cards). [97.9% of FluMist recipients and 97.9% of placebo recipients.] Other Adverse Events in Adults In addition to the solicited events, participants also reported other adverse events that occurred during the course of the clinical trials.For adults 18-49 years of age in the Adult Effectiveness Study, nasal congestion (9.2% FluMist vs 2.2% placebo), rhinitis (6.3% FluMist vs 3.1% placebo), and sinusitis (4.1% FluMist vs 2.2% placebo) were reported significantly more often by FluMist recipients compared to placebo recipients. Package Insert (Circular) 16 June 2003 Page 15 of 19 ADVERSE EVENT REPORTING Reporting by vaccine recipients or the parents/guardians of vaccinees and health care providers of all adverse events occurring after vaccine administration is encouraged. The U.S. Department of Health and Human Services (DHHS) has established a Vaccine Adverse Event Reporting System (VAERS) to accept all reports of suspected adverse events after the administration of any vaccine. The VAERS toll-free number is 1-800-822-7967. Reporting forms may also be obtained at the FDA web site at: http//www.vaers.org. DOSAGE AND ADMINISTRATION FOR NASAL USE ONLY. DO NOT ADMINISTER PARENTERALLY. FluMist should be administered according to the following schedule: Age Group Vaccination Status Dosage Schedule Children age 5 years through 8 years Not previously vaccinated with FluMist 2 doses (0.5 mL each, 60 days apart ± 14 days) for initial season Children age 5 years through 8 years Previously vaccinated with FluMist 1 dose (0.5 mL) per season Children and Adults age 9 through 49 years Not applicable 1 dose (0.5 mL) per season For healthy children age 5 years through 8 years who have not previously received FluMist vaccine, the recommended dosage schedule for nasal administration is one 0.5 mL dose followed by a second 0.5 mL dose given at least 6 weeks later. Only limited data are available on the degree of protection in children who receive one dose (see CLINICAL PHARMACOLOGY). For all other healthy individuals, including children age 5-8 years who have previously received at least one dose of FluMist, the recommended schedule is one dose. FluMist should be administered prior to exposure to influenza. The peak of influenza activity is variable from year to year, but generally occurs in the U.S. between late December and early March. Because the duration of protection induced by FluMist is not known and yearly antigenic variation in the influenza strains is possible, annual revaccination may increase the likelihood of protection. FluMist must be thawed prior to administration. FluMist may be thawed by holding the sprayer in the palm of the hand and supporting the plunger rod with the thumb (see ADMINISTRATION INSTRUCTIONS); the vaccine should be administered immediately thereafter. Alternatively, FluMist may be thawed in a refrigerator and stored at 2-8oC (36-46oF) for no more than 24 hours prior to use. When thawed for administration, FluMist is a colorless to pale yellow liquid and is Package Insert (Circular) 16 June 2003 Page 16 of 19 clear to slightly cloudy; some proteinaceous particulates may be present but do not affect the use of the product. Approximately 0.25 mL (i.e., half of the dose from a single FluMist sprayer) is administered into each nostril while the recipient is in an upright position. Insert the tip of the sprayer just inside the nose and depress the plunger to spray. The dose-divider clip is removed from the sprayer to administer the second half of the dose (approximately 0.25 mL) into the other nostril. Once FluMist has been administered, the used sprayer should be disposed of according to the standard procedures for biohazardous waste products. ADD PDF PICTORIAL HERE (see pictorial, page 19). HOW SUPPLIED FluMist is supplied for intranasal delivery in a package of 10 pre-filled, single-use sprayers (NDC 66019-100-01). STORAGE STORE AT OR BELOW -15°C (5°F). DO NOT REFREEZE AFTER THAWING. UPON RECEIPT, FluMist SHOULD BE IMMEDIATELY STORED AT -15°C (5°F) OR BELOW. FluMist may be stored in a non-frost-free freezer to be maintained continuously at –15oC (5oF) or below. Storage of FluMist in a frost-free freezer should be avoided because the temperature could cycle above –15oC (5oF) and can therefore negatively impact the stability of the product. FluMist may be thawed in a refrigerator and stored at 2-8oC (36-46oF) for no more than 24 hours prior to use. For information regarding product storage and stability under conditions other than those recommended, call 1-800-411-0086. REFERENCES 1. Centers for Disease Control and Prevention. Prevention and control of Influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2003; 52 (No.RR-8):1-34. 2. Murphy BR, Coelingh KC. Principles underlying the development and use of live attenuated cold-adapted influenza A and influenza B virus vaccines. Viral Immunol. 2002;15:295-323. Package Insert (Circular) 16 June 2003 Page 17 of 19 3. Jin H, et al. Multiple amino acid residues confer temperature sensitivity to human influenza virus vaccine strains (FluMist) derived from cold-adapted A/Ann Arbor/6/60. Virology. 2003;306:18-24. 4. MedImmune data on file. 5. Monto AS, Sullivan KM. Acute respiratory illness in the community. Frequency of illness and the agents involved. Epidemiol Infect. 1993;110:145-160. 6. Sullivan KM. Health impact of influenza in the United States. Pharmacoeconomics. 1996;9 Suppl. 3:26-33. 7. Barker WH, Mullooly JP. Impact of epidemic Type A influenza in a defined adult population. Am J Epi. 1980; 112:798-811. 8. Thompson WW, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289:179-186. 9. Murphy BR, Clements ML. The systemic and mucosal immune response of humans to influenza A virus. Curr Topics in Micro Immun. 1989;146:107-116. 10. McMichael AJ, et al. Cytotoxic T-cell immunity to influenza. N Engl J Med. 1983;309: 13-17. 11. Belshe RB, et al. Correlates of immune protection induced by live, attenuated, coldadapted,trivalent, intranasal influenza virus vaccine. J Infect Dis. 2000a;181:1133-1137. 12. Treanor JJ, et al. Evaluation of trivalent, live, cold-adapted (CAIV-T) and inactivated (TIV) influenza vaccines in prevention of virus infection and illness following challenge of adults with wild-type influenza A (H1N1), A (H3N2), and B viruses. Vaccine. 2000;18:899-906. 13. Belshe RB, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine in children. N Engl J Med. 1998;338:1405-1412. 14. Belshe RB, et al. Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine. J Peds. 2000b;136:168-175. 15. Nichol KL, et al. Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults. JAMA. 1999;282:137-144. 16. Vesikari T, et al. A randomized, double-blind, placebo-controlled trial of the safety, transmissibility and phenotypic stability of a live, attenuated, cold-adapted influenza virus vaccine (CAIV-T) in children attending day care. Presented at the 41st Annual Package Insert (Circular) 16 June 2003 Page 18 of 19 Interscience Conference on Antimicrobial Agents and Chemotherapy, (Chicago, IL). 2001. 17. Longini IM, et al. Estimating household and community transmission parameters for influenza. Am J Epidemiol. 1982;115:736-751. Manufactured by: MedImmune Vaccines, Inc. Gaithersburg, MD 20878 Marketed by: MedImmune Vaccines, Inc. Gaithersburg, MD 20878 and Wyeth Vaccines Philadelphia, PA 19101 Component No. Issue Date: U.S. Government License No. 1652 Package Insert (Circular) 16 June 2003 Page 19 of 19 ADMINISTRATION INSTRUCTIONS

Needle-phobics wishing to fend off the flu have a new, injection-free option this season. But they may have to look hard to find it and pay through the nose for it. Five months after the Food and Drug Administration approved FluMist, the nation's first nasal vaccine, few local clinics are offering it, and despite a $25 million TV and print advertising blitz, few patients are asking for it.

"When it first came out, people were like 'Oh wow. This is going to be a great thing. But the practicality is, it is not that appealing financially and there are more risks,'" said Louisville physician David Nuhfer, one of the few Boulder County doctors offering the vaccine. While a traditional influenza shot costs around $15 and is often covered by insurance, FluMist costs $65 or more and must typically be paid for out-of-pocket. Because the nasal vaccine is made from a weakened live vaccine rather than a dead one, like the shot, there is some risk that a person with a compromised immune system could get sick from it, or a healthy person could get the shot and pass the virus on to a sick loved one.

The vaccine is only recommended for healthy people age 5 to 49. "Potentially, you could pass it on to grandma who has cancer," said Nuhfer, who plans to carefully screen anyone inquiring about the nasal vaccine. The upside of the shot, doctors say, is that it may lure shot-averse adults and kids who might otherwise skip their influenza vaccine altogether. "There are a lot of people who don't get a flu shot at all because they are petrified of needles," said Jennifer Freeman, of Boulder-based Passport Health, a traveling clinic that is offering the shot.

There are, however, other problems with the vaccine.

On Friday, Wal-Mart Stores Inc. announced that the company was backing out of plans to offer the vaccines at 1,000 of its stores because several state pharmacy boards have been raising questions about whether it is legal or not for pharmacists to administer it. The Colorado Board of Pharmacy is currently considering the matter. The new vaccine must also be stored frozen and shipped directly to the point of delivery, which can make it difficult to offer at mass immunization clinics.

Despite the drug's seemingly rocky start, and the tumble its stock took — from about $33.50 per share Wednesday to $28.64 per share Monday — at the news of Wal Mart's change of heart, officials at Maryland-based MedImmune Inc., which makes FluMist, say they are still optimistic. Recent television ads and full-page ads in Newsweek and other publications are expected to spike interest.

"It is still very early in the season," said MedImmune spokesperson Jamie Lacey, noting that more than 14,000 outlets nationwide are offering the vaccine. Ned Cologne, chief medical officer for the Colorado Department of Public Health and Environment sees FluMist is an intriguing new breakthrough that could someday change the way vaccines are administered. "It will be interesting to watch," he says. If it will help more people get immunized, that's great, he says.

DENVER - If you've got your mind set on the needle-less flu vaccine, you might be disappointed at some flu clinics because the new nasal flu mist is hard to come by in Colorado. It's expensive, needs to stay frozen and isn't recommended for everyone. Unlike the conventional flu shot where the virus is killed, the nasal flu mist contains live virus. The live virus has been attenuated, meaning it's genetically altered so it won't make you sick, but there have been some reports of what's called viral shedding.

In viral shedding, some of the virus can escape into the air if you sneeze or blow your nose. And some people can have a reaction to it. The nasal vaccine's greatest obstacle though is that it's recommended only for healthy people ages 5 to 49. Pregnant women can't use it, and neither can people with chronic diseases like asthma and diabetes. Plus, it has to be frozen right up until you use it.

"That's why you're not going to be seeing it in mass immunization clinics because the vaccine needs to be frozen and continuously frozen because it is a live-virus vaccine," said Roberta Smith of Immunization Coalition. Cost is also an issue. While a traditional flu shot costs around $15 and is often covered by insurance, FluMist costs $65 or more and must typically be paid for out-of-pocket. There are other problems with the vaccine. Last week, Wal-Mart Stores Inc. said the company was backing out of plans to offer the vaccines at 1,000 of its stores because of questions about whether it is legal for pharmacists to administer it. The Colorado Board of Pharmacy is currently considering the matter.

The makers of the nasal spray FluMist say they are still optimistic. "It is still very early in the season," said MedImmune Inc. spokesperson Jamie Lacey, noting that more than 14,000 outlets nationwide are offering the vaccine. Ned Cologne, chief medical officer for the Colorado Department of Public Health and Environment, said FluMist could someday change the way vaccines are administered. "It will be interesting to watch," he said. "But my feeling as a patient is: The shot is quick. It's safe. It's effective." The government approved the nation's first nasal flu vaccine five months ago.

Safety concerns were also an issue. FluMist is a live vaccine, made from attenuated flu viruses. It can theoretically give people, especially those with weakened immune systems, a mild case of the flu. MedImmune executives said the chances of this were extremely low but that somehow consumers and doctors had gotten misperceptions about the vaccine's safety.

Maryland biotechnology company MedImmune decreased its sales forecast for its new, needle-free flu vaccine FluMist from up to $140 million to just $55 million. The company has hired a consultant to determine why the product failed to generate sales this fall. Since FluMist involves a live vaccine while injected flu vaccines involve a dead flu virus, some doctors are advising against its use due to fears that it could cause the flu. MedImmune will reintroduce FluMist next fall with a lower price and with an emphasis on the product's safety and convenience. Another detrimental fact keeping sales of FluMist below expectations is a lack of approval for the product to treat children under the age of five years or adults over the age of 49 years; MedImmune expects approval for these segments of the market, who are most vulnerable to the flu, by 2006.

I wanted to take some pictures to the one hour photo in Krogers today, but remembered they are listed as giving the Flu Mist vax. So, I called them and was transferred to the pharmacy.

I spoke with a pharmacist and asked her what precautions the store was taking to protect the immunocompromised from the live flu vaccine being shed by Flumist recipients. She says, (get this!), "The manufacturer has provided us with a wall barrier to put up." Stifling my laugh I said, "What happens when those people go out into the store and are sneezing on the groceries?" She pauses and asks me to hold on. I'm on hold for several minutes when she comes back and says "The manufacturer tells us that even when a person sneezes after getting the flumist, it has already been absorbed and won't be spread."

I say, "Then why does the package insert say under Precautions that 'Flumist recipients should avoid close contact with immunocompromised individuals for at least 21 days'?"

She again pauses and says, "Hold on, I'll check into that." I'm on hold for at least 5 minutes then get disconnected. So I call back and get a different pharmacist who won't let me speak to the original one. So I ask her the same question. I told her I am concerned for myself (asthma) and those of us who shouldn't be in contact with flumist recipients. She again spouts about the wall barrier. I say, "But this is an airborne virus." (Double DUH!!) She says the manufacturer has assured them that even if someone sneezes on them when they give the vaccine, that it has already been absorbed (in nanoseconds I assume!) and that they themselves shouldn't be concerned. HA! They may be fools, but I'm not! : )

She tries to tell me that only those who live in close contact 24/7 need be concerned (why though, if it isn't spread after it's given?) They're contradicting themselves coming and going! I asked her what the difference was with me being in a store where people are sneezing all over the produce that I may be purchasing and living with someone who is doing the same??

She said it's no different than going into a doctor's office where it's been given (excuse me, but even if I did go to one, I don't buy my groceries at the doctor's office!)

She had no answers. All she had to offer was what the "manufacturer" had assured them was ok and she said "Long term studies show it is safe to the population." But in right before that she says they haven't even given any flumist there at Krogers and she doesn't know anyplace that has actually given it because it is so expensive and because it's brand new no one expects it to be used anyway!!!!!

Idiots... they have no idea what they are doing and when questioned they babble on and spout what the "manufacturer" has told them to say without truly knowing the facts!

Kay

I forgot to add the kicker to my last post... After talking with the 2nd pharmacist ad nauseum about the risks to the immunocompromised, she says, "Well, the worst thing that could happen to you is you would get the flu." It was then I realized I was up against a genius, thanked her for her time and hung up!

Does This Smell Bad?

Health Sciences Institute e-Alert

December 10, 2003

Dear Reader,

You've probably heard the news by now: Doctors are running low on flu vaccines and are expected to run out completely before the flu season winds down. In one of the TV reports I saw, the commentator asked, "How could this happen?" And I had to laugh. How could it happen?

Hmmm... let's put on our thinking caps and try real hard to figure it out. Could it possibly be because nearly every TV news broadcast for the past month has been saying that this will be the worst flu season in years and everyone needs to drop what they're doing - RIGHT NOW! - and go get a flu shot?

Making this news all the more dire is the fact that the final drop of flu vaccine has already been shipped out, so once the vaccine supply is used up, no more vaccine can be produced until next year. But before you barricade yourself in your home, vowing to stay safe inside until the flu season has passed, rest assured that there JUST HAPPENS to be an alternative to the dwindling vaccine supplies.

-------------------------------------------------------------- Come and get it! --------------------------------------------------------------

Remember FluMist? It's the nasal-spray flu vaccine I first told you about in the e-Alert "Nose Candy" (7/8/03). Unlike the conventional flu shot, which contains inactivated flu strains, FluMist contains three living flu strains. The Centers for Disease Control (CDC) calls FluMist "live attenuated influenza vaccine" or LAIV. In other words, the three strains are diluted. They're alive as you or me, but watered down.

Now - a show of hands - how many would feel comfortable inhaling not one, not two, but THREE LIVING flu strains? Not too many, is my guess. Which is probably one of the main reasons why ABC News has described sales of FluMist as "disappointing." Disappointing so far, anyway.

According to the Washington Post, the CDC gave FluMist a nice little boost last week when a statement was released "reminding" the public that FluMist is an appropriate alternative to the flu shot for those who are both healthy and between the ages of 5 and 49. Then on Monday, CDC director Dr. Julie Gerberding made appearances on several national news broadcasts (including ABC and CNN) and mentioned that a large supply of FluMist is still available.

Now is it just me and my cynical streak, or does it seem somehow to be a very, let's say "interesting," coincidence that the country has been plunged into this supposedly dire emergency of vaccine shortage in the same year that a major new vaccine product is launched? No one I know has said they haven't been able to get a flu shot. And I haven't read about any doctors turning away patients who have requested a shot. But if the CDC says the supply is low, then I suppose the supply is low. And if the CDC says that the supply of FluMist is high, then I'm sure the supply is high.

What Dr. Gerberding didn't mention is that FluMist costs more than twice the amount of the flu shot. And because of this much steeper cost, many insurance companies won't offer coverage for FluMist. But that's only part of the FluMist problem.

-------------------------------------------------------------- Pig in a poke --------------------------------------------------------------

As I stated in the July e-Alert, there's a long list of potential problems with FluMist, but one of the key problems is the fact that those who decide to sniff living viruses into their heads instantly become infected by the flu. The immune system then responds by creating more antibodies that, in theory, will fight off any full-strength flu strains that might come along. But in the meantime, there's a possibility that those who are recently FluMisted could be (I'll bet you already guessed it) contagious!

Nice. Just what we need in the middle of a supposed flu epidemic: more contagious people running around.

Of course, the makers of FluMist (MedImmune, a subsidiary of the drug giant Wyeth) play down the possibility of their product spreading the flu, stating that only a very small percentage of FluMist users will actually transmit a virus. Nevertheless, according to a report in Knight-Ridder Newspapers, the CDC cautions those who get a FluMist vaccine to stay away from people with vulnerable immune systems, such as the elderly or those struggling with diseases, for one week. But is one week long enough? Some hospitals are telling their personnel to allow three full weeks between their FluMist vaccine and contact with hospital patients.

Why the discrepancy? My guess is that this is such a new vaccine that no one really knows the parameters yet. Nevertheless, the CDC seems to be going out of their way to help MedImmune move their struggling product.

Add to that; the CDC web site states: "The optimal time to receive influenza vaccine is usually in October or November." So if they're using the same calendar I'm using, we're already 10 days past the optimal usage period.

And add to that; the people who supposedly need a flu vaccine the most - the elderly, and those with immune system diseases - shouldn't be taking FluMist at all. The FDA hasn't approved it for them. So the CDC is pressing those who are least vulnerable to the flu to run out and get a snootful of this expensive and relatively untested product, even though it's almost two weeks past the optimal timing for the vaccine to even work!

Does any of this smell bad to you?"The Vaccine That Missed" Washington Post (www.washingtonpost.com) (01/23/04) P. E1; Barbaro, Michael

The true cost of the influenza vaccine nasal spray FluMist is becoming clearer, as Wyeth has announced that it took a $20 million charge to write off the FluMist doses it produced with MedImmune but was unable to sell in 2003. Though the flu season was unusually early and relatively severe, Wyeth and MedImmune were only able to sell one-fourth of the FluMist they had originally expected to sell, resulting in 2003 sales of just $15.3 million, which analysts say corresponds to fewer than 1 million doses sold. The poor sales underline the difficulty facing vaccine makers in producing a big seller, even under positive conditions for the product, especially as FluMist was much more expensive than the injected version of the vaccine. Wyeth said on Thursday that it is working with MedImmune to develop a new marketing and sales strategy for FluMist in 2004, with analysts suggesting that they may agree to cut the price for the nasal spray vaccine to a losing figure in order to build demand for future flu seasons.

WEDNESDAY, Feb. 25 (HealthDayNews) -- When the U.S. Food and Drug Administration gave approval last year to a new nasal spray flu vaccine called FluMist, some analysts predicted it could become a blockbuster. Instead, sales sank like a stone. Appearing before a federal health panel on Tuesday, officials from Maryland-based MedImmune Inc., the maker of FluMist, said sales have been dismal. Only one million of five million doses have been sold, despite a flu season marked by an usually early and harsh start, The New York Times reports. "Our initial launch was very disappointing," Dr. Peter A. Patriarca, of MedImmune, told the panel, the Advisory Committee on Immunization Practices. The 15-person panel is appointed by the U.S. Department of Health and Human Services to guide the Centers for Disease Control and Prevention on recommendations for influenza and a number of other immunizations, according to the Times. Not even a shortage of traditional flu vaccines could boost sales of FluMist, approved for healthy people ages 5 to 49. The drug companies that make traditional vaccines produced 87 million flu doses for this season. But because the season began in October, leading to high demand for flu shots, the manufacturers said they had sold all their supplies to distributors by December.

Patriarca attributed FluMist's sagging sales to a series of factors, including price. Doctors charged their patients up to $150 for FluMist, he said. Not even a rebate program offered by MedImmune could jumpstart sales, the Times reports.

A new study finds a possible link between a different nasal flu vaccine and Bell's palsy, a temporary paralysis of the facial muscles. Researchers who were looking into the cause of an unusual number of cases of Bell's palsy in Switzerland began noticing a connection with people who had used a nasal vaccine called Nasalflu. Bell's palsy is a neurological paralysis of one side of the face that can last from weeks to months, but doesn't normally have any permanent effects. The study concludes that Nasalflu, which was used only in Switzerland but was pulled from the market several years ago, could be a possible cause of Bell's palsy.

"At this point these are hypothetical conclusions -- no cause has been determined as to the reason why these people contracted Bell's palsy," says Dr. Robert Steffen, of the University of Zurich's Collaborating Centre for Traveller's Health, and one of the study's authors. "What we were able to do is prove a strong association between the flu vaccine and Bell's palsy, but we cannot demonstrate why at this point."

The study appears in the Feb. 26 issue of the New England Journal of Medicine. Health experts, however, don't see a link between the potential problems associated with Nasalflu, and FluMist. "It would be hard to see an association," says Ira M. Longini Jr., of Emory University. "I just don't know where it would be. These are completely different vaccines: one [FluMist] is a live attenuated and cold-adapted virus and one [Nasalflu] is deactivated -- totally different." Nasalflu was manufactured by the Swiss company Berna Biotech AG, and was used in Switzerland in the 2000-2001 flu season. It was pulled by the company when reports of possible Bell's palsy cases began surfacing.

Wednesday, September 26, 2007Moldy FluMist Holds Up Final FDA Approval

by Barbara Loe Fisher

Until June 2003, when the FDA approved the first live virus flu vaccine, FluMist, the only flu vaccine that was used in the US was the killed or inactivated flu vaccine injected into the arm. FluMist manufactured by MedImmune was the first vaccine designed to be squirted up the nose and given to healthy children and adults. Generally, Americans have not been enthusiastic about squirting live virus flu vaccine up their noses. Call it irrational. Call it the "yuck" factor. Call it instinct. FluMist has largely remained a non-starter.

The fact that the FDA had to recently slap MedImmune on the hands after inspectors reportedly found excessive amounts of mold and bacteria during early stages of the production process of FluMist doesn't help. A September 10, 2007 Washington Post article said the company was cited for "significant deviations for current good manufacturing practice." http://www.washingtonpost.com/wp-dyn/content/article/2007/09/09/AR2007090901 612.html?nav=rss_business

In pre-licensure clinical trials of FluMist, there was an increased risk of asthma, upper respiratory infections, musculoskeletal pain, otitis media and croup for some children and an increased risk for upper respiratory symptoms in adults after inhaling the live vaccine. FluMist contains attenuated live flu viruses and poses a risk of transmission of live flu virus from the recently vaccinated to close contacts. When I was sitting on the FDA Vaccines and Related Biological Products Advisory Committee in 2002, I voted "no" when asked if safety had been proven. http://www.fda.gov/ohrms/dockets/ac/02/transcripts/3912t1-03.pdf

Among other things, I said "The fact that live vaccine flu virus is shed in 80 percent of recipients poses an additional risk for our population at large, particularly for immune compromised individuals across all age groups. The outstanding questions about the true rate of transmission of vaccine strain viruses among children needs to be clarified as does the retention of the attenuation of shed viruses and the high frequency of nucleotide changes. Because this live virus nasal vaccine is not indicated for high risk health groups, which have historically been the targeted populations to receive flu vaccine, it's a very serious step to move to the use of a live virus vaccine for the majority of healthy individuals, and a standard for proof of safety must be very high. I don't think that standard has yet been met by the data which have been presented so far."

Initially, the FDA approved the vaccine for healthy children over 5 and adults under 49. Both MedImmune and vaccine distributor, Wyeth, thought they had a blockbuster on their hands. In the summer and fall of 2003, the companies launched a $100 million ad campaign that featured Wal Marts offering to squirt the vaccine up the noses of shoppers.(MedImmune, Inc. [Investors] News Releases. September 10, 2003 "FluMist Available in Pharmacies This Fall."). At a cost of between $46 and $150 a dose, the companies were projecting between $120 million and $140 million in sales. But by late October 2003, it became apparent that few of the four million doses of FluMist that MedImmune had produced were being purchased. By January 2004, the company was trying to give it away. MedImmune has been trying to capture market share for FluMist ever since the disastrous FluMist debut in the 2003-2004 flu season.

Now, the FDA has given MedImmune (recently acquired by British drug firm Astra Zeneca) another chance by approving FluMist for healthy children over two years. But still, the warning remains about not giving FluMist to anyone with asthma or children under five with a history of wheezing. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01705.html

What healthy adults and parents of healthy children need to ask themselves is: why do healthy people need to deliberately inhale live flu viruses when the majority of healthy people don't get that sick from the flu and recover without any complications? Keep reading NVIC's E-News for further reports on the Flu and You as the flu season approaches and the Flu Patrol gears up to scare the living daylights out of you so you inhale deeply or roll up your sleeve without giving it a second thought.

In the News:

"The FDA sent the Gaithersburg firm a lengthy warning letter in May, citing "significant deviations from current good manufacturing practice." Agency officials were concerned that MedImmune had not properly followed up after excessive levels of mold and bacteria were found during early stages of the production process. The FDA said the vaccine had not been contaminated. The FDA's warning letter has held up shipments of FluMist. It also put on hold MedImmune's efforts to win regulatory approval for use of the vaccine by children under 5. Expanding the vaccine's use in that important market has been a cornerstone of the firm's efforts to boost the prospects for FluMist, which has not been a hit in the marketplace. It is now approved only for people ages 5 to 49. FDA and MedImmune officials said the process to win approval for use by younger children could now continue. Less than two weeks before the warning letter was issued, an FDA advisory panel unanimously agreed that FluMist worked in children under 5. The panel was mixed on whether FluMist was safe enough for children younger than 2." - Michael Rosenwald, Washington Post (September 10, 2007) http://www.washingtonpost.com/wp-dyn/content/article/2007/09/09/AR2007090901612.html?nav=rss_business

"The U.S. Food and Drug Administration today approved expanding the population for use of the nasal influenza vaccine FluMist to include children between the ages of 2 and 5. Approval for the vaccine, which contains a weakened form of the live virus and is sprayed in the nose, was previously limited to healthy children 5 years of age and older and to adults up to age 49.......Children under the age of 2 should not receive FluMist because there was an increased risk of hospitalization and wheezing for this age group during the clinical trials. Commonly observed adverse events from the vaccine were generally mild and most often included runny nose and/or nasal congestion, as well as a slight fever in children 2 to 6 years of age. FluMist should not be administered to anyone with asthma or to children under the age of 5 years with recurrent wheezing because of the potential for increased wheezing after receiving the vaccine. People who are allergic to any of FluMist's components, including eggs or egg products, should also not receive the vaccine....." - FDA Press Release (September 19, 2007) http://www.fda.gov/bbs/topics/NEWS/2007/NEW01705.html MedImmune Says FluMist Problems